Linking clinical trials and observational data to decision analytic modeling is one way to help answer pressing questions in HIV disease management. Trained as a biostatistician, Elena Losina, Ph.D. has worked on the "Cost-effectiveness of Preventing AIDS Complications" or "CEPAC" project led by Kenneth A. Freedberg, M.D., MSc. during the last six years, first as a doctoral student and then as a principal biostatistician. The proposed K25 Award will provide her with resources to extend her expertise in decision analytic modeling and to complete the project: "Modeling Sequential Antiretroviral Therapy in HIV." Combination antiretroviral therapy (ART) is the standard of care for HIV disease, but the optimal management of patients who have failed a first-line ART regimen remains controversial. One of the unresolved questions is how to define treatment failure and when to switch to another regimen. Early intensification of a failing regimen is also of unclear utility. The evolving data addressing these important issues are based on short-term outcomes of randomized clinical trials, while the long-term implications of sequential strategies for changing ART regimens remain unknown. Dr. Losina will build upon the CEPAC decision analysis model to compare different strategies of sequential ART for management of HIV-infected patients by achieving the following four specific aims: (1) to perform a formal meta-analysis of the efficacy of sequential combination ART regimens for HIV-infected patients who have failed at least one combination ART regimen; (2) to revise a computer simulation model to incorporate the effect of early intensification of a combination ART regimen and to examine its impact on the effectiveness of sequential ART strategies and the rate of disease progression; (3) to examine what degree of efficacy, in terms of immune reconstitution, salvage ART must have to be both effective and cost-effective compared with stopping therapy; and (4) to investigate the impact of different ART efficacy components, such as viral suppression and immune reconstitution, on the quality-adjusted life expectancy of HIV-infected patients. Dr. Losina will pursue formal didactic training in decision analysis while continuing to work with her primary mentor, Dr. Freedberg, and with a diverse group of experienced investigators in the areas of HIV disease, clinical epidemiology and decision sciences. This award will provide critical insight into the optimal strategies for managing HIV infection and will provide Dr. Losina with a solid foundation for development as an independent and productive investigator.